WIP1 deficiency inhibits HTLV-1 Tax oncogenesis: novel therapeutic prospects for treatment of ATL?

in Retrovirology (2012), 9(1), 115

Attenuation of p53 activity appears to be a major step in Human T-lymphotropic virus type 1 (HTLV-1) Tax transformation. However, p53 genomic mutations are late and rather infrequent events in HTLV-1 ... [more ▼]

Attenuation of p53 activity appears to be a major step in Human T-lymphotropic virus type 1 (HTLV-1) Tax transformation. However, p53 genomic mutations are late and rather infrequent events in HTLV-1 induced Adult T cell leukemia (ATL). The paper by Zane et al. shows that a mediator of p53 activity, Wild-type p53-induced phosphatase 1 (Wip1), contributes to Tax-induced oncogenesis in a mouse model. Wip1 may therefore be a novel target for therapeutic approaches. [less ▲]

Répétition, isotopie, tensivité

in Nouveaux Actes Sémiotiques (2012)

Impact des services publics et sociaux sur le revenu des ménages belges

in D'autres Repères (2012)

Comment enseigner les médias en secondaire ?

Scientific conference (2012, December 20)

Clinical recognition and aspects of the cerebral folate deficiency syndromes

in Clinical Chemistry & Laboratory Medicine (2012)

Genomic Association Screening Methodology for High-Dimensional and Complex Data Structures: Detecting n-Order Interactions

Doctoral thesis (2012)

We developed a data-mining method, Model-Based Multifactor Dimensionality Reduction (MB-MDR) to detect epistatic interactions for different types of traits. MB-MDR enables the fast identification of gene ... [more ▼]

We developed a data-mining method, Model-Based Multifactor Dimensionality Reduction (MB-MDR) to detect epistatic interactions for different types of traits. MB-MDR enables the fast identification of gene-gene interactions among 1000nds of SNPs, without the need to make restrictive assumptions about the genetic modes of inheritance. This thesis primarily focused on applying Model-Based Multifactor Dimensionality Reduction for quantitative traits, its performance and application to a variety of data problems. We carried out several simulation studies to evaluate quantitative MB-MDR in terms of power and type I error, when data are noisy, non-normal or skewed and when important main effects are present. Firstly, we assessed the performance of MB-MDR in the presence of noisy data. The error sources considered were missing genotypes, genotyping error, phenotypic mixtures and genetic heterogeneity. Results from this study showed that MB-MDR is least affected by presence of small percentages of missing data and genotyping errors but much affected in the presence of phenotypic mixtures and genetic heterogeneity. This is in line with a similar study performed for binary traits. Although both Multifactor Dimensionality Reduction (MDR) and MB-MDR are data reduction techniques with a common basis, their ways of deriving significant interactions are substantially different. Nevertheless, effects on power of introducing error sources were quite similar. Irrespective of the trait under consideration, epistasis screening methodologies such as MB-MDR and MDR mainly suffer from the presence of phenotypic mixtures and genetic heterogeneity. Secondly, we extensively addressed the issue of adjusting for lower-order genetic effects during epistasis screening, using different adjustment strategies for SNPs in the functional SNP-SNP interaction pair, and/or for additional important SNPs. Since, in this thesis, we restrict attention to 2-locus interactions only, adjustment for lower-order effects always (and only) implies adjustment for main genetic effects. Unfortunately most data dimensionality reduction techniques based on MDR do not explicitly require that lower-order effects are included in the ‘model’ when investigating higher-order effects (a prerequisite for most traditional, especially regression-based, methods). However, epistasis results may be hampered by the presence of significant lower-order effects. Results from this study showed hugely increased type I errors when main effects were not taken into account or were not properly accounted for. We observed that additive coding (the most commonly used coding in practice) in main effects adjustment does not remove all of the potential main effects that deviate from additive genetic variance. In addition, also adjusting for main effects prior to MB-MDR (via a regression framework), whatever coding is adopted, does not control type I error in all scenarios. From this study, we concluded that correction for lower-order effects should preferentially be done via codominant coding, to reduce the chance of false positive epistasis findings. The recommended way of performing an MB-MDR epistasis screening is to always adjust the analysis for lower-order effects of the SNPs under investigation, “on-the-fly”. This correction avoids overcorrection for other SNPs, which are not part of the interacting SNP pair under study. Thirdly, we assessed the cumulative effect of trait deviations from normality and homoscedasticity on the overall performance of quantitative MB-MDR to detect 2-locus epistasis signals in the absence of main effects. Although MB-MDR itself is a non-parametric method, in the sense that no assumptions are made regarding genetic modes of inheritance, the data reduction part in MB-MDR relies on association tests. In particular, for quantitative traits, the default MB-MDR way is to use the Student’s t-test (steps 1 and 2 of MB-MDR). Also when correcting for lower-order effects during quantitative MB-MDR analysis, we intrinsically maneuver within a regression framework. Since the Student’s t-statistic is the square root of the ANOVA F-statistic. Hence, along these lines, for MB-MDR to give valid results, ANOVA assumptions have to be met. Therefore, we simulated data from normal and non-normal distributions, with constant and non-constant variances, and performed association tests via the student’s t-test as well as the unequal variance t-test, commonly known as the Welch’s t-test. At first somewhat surprising, the results of this study showed that MB-MDR maintains adequate type I errors, irrespective of data distribution or association test used. On the other hand, MB-MDR give rise to lower power results for non-normal data compared to normal data. With respect to the association tests used within MB-MDR, in most cases, Welch’s t-test led to lower power compared to student’s t-test. To maintain the balance between power and type I error, we concluded that when performing MB-MDR analysis with quantitative traits, one ideally first rank-transforms traits to normality and then applies MB-MDR modeling with Student’s t-test as choice of association test. Clearly, before embarking on using a method in practice, there is a need to extensively check the applicability of the method to the data at hand. This is a common practice in biostatistics, but often a forgotten standard operating procedure in genetic epidemiology, in particular in GWAI studies. In addition to the presentation of extensive simulation studies, we also presented some MB-MDR applications to real-life data problems. These analyses involved MB-MDR analyses on quantitative as well as binary complex disease traits, primarily in the context of asthma/allergy and Crohn’s disease. In two of the presented analyses, MB-MDR confirmed logistic regression and transmission disequilibrium test (TDT) results. Part of the aforementioned methodological developments was initiated on the basis of observations of MB-MDR behavior on real-life data. Both the practical and theoretical components of this thesis confirm our belief in the potential of MB-MDR as a promising and versatile tool for the identification of epistatic effects, irrespective of the design (family-based or unrelated individuals) and irrespective of the targeted disease trait (binary, continuous, censored, categorical, multivariate). A thorough characterization of the different faces of MB-MDR this versatility gives rise to is work in progress. [less ▲]

Study of the physiological component involved in the development of crown rot in bananas and the role of phenolics in susceptibility variation mechanisms

Doctoral thesis (2012)

Crown rot is a post-harvest disease caused by a broad unspecific and opportunistic parasitic complex, which affects the quality of export bananas in Cameroon, as well as in most of the production areas ... [more ▼]

Crown rot is a post-harvest disease caused by a broad unspecific and opportunistic parasitic complex, which affects the quality of export bananas in Cameroon, as well as in most of the production areas around the world. The originality of this research is that it is sets out, not only to investigate on the conditions surrounding the development of the disease and the variable factors of fruit’s susceptibility, but equally to characterize the phenolic content of the banana crown with differential susceptibility levels. The study therefore aims at showing the influence of abiotic and biotic factors on the fruit’s physiological component at harvest and the involvement of phenolic compounds in the mechanism staked in fruit’s susceptibility variations to this pathology. At the end of this study, it appears that abiotic and biotic factors influence the fruit’s physiological component at harvest, affecting thus its susceptibility level and therefore favours the development of crown rot disease. The reliability of internal necrosis surface (INS) assessments method was improved. The influence of abiotic factors (production area and harvest date) on fruit susceptibility was demonstrated without season influence. Fruits grown in high altitudes (Ekona, 500 m) were less susceptible to crown rot than the ones grown in low altitudes (Dia-Dia, Koumba, 80 m). It was noticed that at certain harvest dates within the rainy season, fruit susceptibility was higher in plantations with low altitudes. Concerning biotic factors, Mycosphaerella leaf spot disease’s influence was shown in two geographical areas. In Cameroon, black leaf streak disease significantly influenced banana’s sensitivity to crown rot (P< 0.001). In Guadeloupe, Sigatoka disease had no effect (P> 0.05) on banana’s susceptibility to the development of crown rot disease. The influence of the source-sink ratio variations, an abiotic factor, on fruit physiology could explain these differences. The influence of severe source-sink ratio modification on fruit susceptibility to crown rot was shown. Fruits with low source-sink ratio were the most susceptible. Bananas of extreme modalities (12leaves/1hand, 1leaf/8hands) and with differential susceptibility (S-, S+) to crown rot were used for the biochemical characterization of their phenolic content at two stages: the day of harvest before inoculation (dhbi) and 13 days post-inoculation (13dpi) by chromatographic methods (GC-MS, HPLC, LC-MS). Dopamine was identified as the major secondary metabolite (phenolic alkaloid) in banana crown. Norepinephrine and normetanephrine levels were high in the dhbi, especially in the S+ crowns. Hydroxycinnamic acids (ferulic acid, coumaric acid and their derivatives) and other unidentified compounds were accumulated in highly significant quantities (P <0.001) in the dhbi in the less susceptible crown (S-) as compared to the susceptible ones (S+), with decreased 13dpi mostly in the susceptible fruits (S+). These results suggest a possible role of these phenolics in banana crown biochemical defense. However, the main role of each phenolic detected in the susceptibility variations mechanism remains unclear. This study is the starting point to understanding the function(s) of phenolics in banana crown defense. This is a pioneer study on the influence of abiotic and biotic factors on the banana fruit’s physiological component at harvest through the assessment of their incidence on crown rot development. This work appears to be the first to link the level of fruit’s susceptibility at two stages (dhbi and13dpi) with their crown phenolic content. [less ▲]

Achromatization of nonimaging Fresnel lenses for photovoltaic solar concentration using refractive and diffractive patterns

Doctoral thesis (2012)

In the field of concentrated photovoltaics, the main disadvantage of lenses compared to mirrors lies in their chromaticity: Snell's law is related to the refractive index which is wavelength dependent ... [more ▼]

In the field of concentrated photovoltaics, the main disadvantage of lenses compared to mirrors lies in their chromaticity: Snell's law is related to the refractive index which is wavelength dependent. Consequently, even for purely collimated beams under normal incidence, the maximum concentration achievable with typical lenses made of PMMA is limited to ~1000×. This maximum value becomes even lower when considering Sun's angular aperture. Since the law of reflection is not wavelength dependent, mirrors can theoretically achieve the thermodynamic limit of concentration which is about 46'000×. This thesis aims at the design and the manufacturing of an achromatic Fresnel lens suitable for photovoltaic solar concentration, i.e. combining high concentration, low production cost and tolerance to manufacturing errors. Firstly, we investigated a hybrid lens made of a refractive lens and a diffractive lens. The investigations showed that the concentration ratio could be multiplied by 4. A full chapter is dedicated to the optimisation of blazed diffraction gratings to finally achieve the design of the diffractive lens. Nevertheless, a bilayer diffractive lens is needed to obtain a high diffraction efficiency which makes the diffractive lens highly sensitive to manufacturing errors and consequently not suitable for photovoltaic solar concentration. Purely refractive achromatic Fresnel doublets were then investigated and several designs were compared. They allow for very high concentration ratios in the case of collimated beams under normal incidence, higher than 100'000×. Therefore, contrary to singlets, Fresnel doublets are much more affected by the angular size of the source than by the chromatic aberration. Moreover, it was shown that they are tolerant to manufacturing error, change of temperature and uncertainty on the refractive index. It emerges from this thesis that the concept of achromatic doublets is a tolerant and low-cost production solution to achieve a highly concentrated white flux. Although bilayer diffractive lenses are not suitable for concentrated photovoltaics, the combination of refractive with diffractive structures seems to be promised to a bright future for spectrum splitting applications, including spectrum splitting for concentrated photovoltaics. [less ▲]

Multi-row approaches to cutting plane generation

Doctoral thesis (2012)

This thesis focuses on the use of cutting-plane techniques to improve general-purpose mixed-integer linear programming solvers. The first topic covered here is a fast separation method for two-row cuts ... [more ▼]

This thesis focuses on the use of cutting-plane techniques to improve general-purpose mixed-integer linear programming solvers. The first topic covered here is a fast separation method for two-row cuts. Two-row cuts are intersection cuts from two rows of a simplex tableau describing the LP relaxation of the problem. This type of cuts recently gathered a lot of attention from the scientific community following a paper by Andersen, Louveaux, Weismantel and Wolsey describing the facets of the underlying two-row model and providing an intuitive geometric classification the the derived cuts. The specificity of the approach adopted here is that it does not rely on an "infinite relaxation" point of view and generate intersection cuts from fixed lattice-free sets. Instead, given a fractional point, it aims at always finding a most violated facet-defining inequality for the two-row model. This can be achieved by optimizing over the polar set of the integer hull of the model. A fast way of performing this is provided, by means of a polyhedron that is equivalent to the polar for that purpose, but has a more compact representation. Moreover, a row-generation algorithm is developed in order to avoid the costly computations of integer hulls of two-dimensional cones. An implementation of the resulting algorithm performs separation of two-row cuts in a few milliseconds on average, on the standard MIPLIB 3 and 2003 testsets. While this two-row separator is quick, the measurements of the computational usefulness of the cuts do not yield satisfactory results. Since all the cuts generated are facet-defining, this might suggest that the underlying two-row models are too weak. This observation prompted the second part of this thesis, an attempt to evaluate the strength of various multi-row relaxations, on small instances, using a generic separator. To that end, a separator is developed, which is able to compute facet-defining inequalities from arbitrary (yet reasonably small) mixed-integer sets. A row-generation approach is again adopted, but this time the slave part consists in the resolution of a mixed-integer problem instead of a closed-form oracle. Some interesting computational tricks are developed, in order to speedup the inherently hard computations. [less ▲]

Déconstruire les stéréotypes pour mieux interagir avec les patients souffrant de la maladie d'Alzheimer

Scientific conference (2012, December 18)